Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria
Markus LangUday S. GanapathyLea MannRana AbdelazizRüdiger W. SeidelRichard GoddardIlaria SequenziaSophie HoenkePhilipp SchulzeWassihun Wedajo AragawRené CsükThomas DickAdrian Richter
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Abstract:
Nα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide [MMV688845, Pathogen Box; Medicines for Malaria Venture; IUPAC: (2R)-N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide)] is a hit compound, which shows activity against Mycobacterium abscessus (MIC90 6.25–12.5 μM) and other mycobacteria. This work describes derivatization of MMV688845 by introducing a thiomorpholine moiety and the preparation of the corresponding sulfones and sulfoxides. The molecular structures of three analogs are confirmed by X-ray crystallography. Conservation of the essential R configuration during synthesis is proven by chiral HPLC for an exemplary compound. All analogs were characterized in a MIC assay against M. abscessus, Mycobacterium intracellulare, Mycobacterium smegmatis, and Mycobacterium tuberculosis. The sulfone derivatives exhibit lower MIC90 values (M. abscessus: 0.78 μM), and the sulfoxides show higher aqueous solubility than the hit compound. The most potent derivatives possess bactericidal activity (99% inactivation of M. abscessus at 12.5 μM), while they are not cytotoxic against mammalian cell lines.Keywords:
Mycobacterium abscessus
Mycobacterium smegmatis
Moiety
Antimycobacterial
Nontuberculous Mycobacteria
Background Considering the importance of the increasing incidence of non-tuberculous mycobacteria, especially Mycobacterium abscessus worldwide, we conducted a study to evaluate the incidence of these diseases in our area. The aim of this study was to evaluate the prevalence of M. abscessus in patients with non-tuberculous mycobacteria. Methods This descriptive study was performed on 18,083 samples isolated from patients with non-tuberculous mycobacteria during 2011-2017 at the Mycobacteriology Research Center (MRC), Tehran, Iran. To identify the Mycobacterium species, a 439 bp fragment of the IS6110 gene was first amplified using primers TB1 and TB2. Samples with a negative polymerase chain reaction (PCR) result were analyzed to investigate non-tuberculosis mycobacteria (NTM), especially M. abscessus using the RFLP method. Results Of the 18,083 samples, 5513 (30.49%, 95% CI, 12.95) strains of Complex Tuberculosis and 236 (1.31%, 95% CI, 1.84) strains of NTM were identified. The mean age of the patients with NTM was 18 years, and most of them were male. The most commonly identified species in this study were M. abscessus type Ι 32 (13.56%, 95% CI, 18.36) and M. abscessus type II 13 (5.51%, 95%CI, 20.04). Conclusion In this study, we observed a high prevalence of Mycobacterium abscessus type 1 in patients. As the treatment protocol for non-TB mycobacteria is different from M. abscessus complex, the diagnosis of these species as soon as possible will be significant for physicians.
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Mycobacterium abscessus is a ubiquitous, rapidly growing species of nontuberculous mycobacteria that colonizes organic surfaces and is frequently associated with opportunistic infections in humans. We report here the draft genome sequence of Mycobacterium abscessus strain M139, which shows genomic features reported to be characteristic of both Mycobacterium abscessus subsp. abscessus and Mycobacterium abscessus subsp. massiliense.
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The incidence of nontuberculous mycobacterial (NTM) infections in cystic fibrosis (CF) patients is increasing, with some CF clinics in the US reporting NTM prevalence upwards of 25%. In addition, the current treatment
regimen for NTM involves long courses of antibiotic cocktails that demonstrate limited efficacy and cause frequent and serious side effects.
Mycobacterium abscessus, in particular, is difficult to treat and correlates with a more rapid decline in lung function compared to Mycobacterium avium complex. Studies with zebrafish and human cell cultures have demonstrated that M. abscessus is more virulent when aggregated into cord-like biofilms, in part because of the decreased ability of phagocytes to efficiently engulf and kill corded M. abscessus compared to diffuse M. abscessus cells. Translating these findings into useful clinical strategies
for treating NTM infections will be greatly aided by 1.) A thorough understanding of the environmental conditions and genetic networks that control NTM aggregation, and 2.) Information about the in vivo aggregation state of NTM during infection. To address item 1, we developed an in
vitro aggregation assay in which NTM such as M. abscessus and the model strain Mycobacterium smegmatis aggregate and disperse regularly in liquid culture. We found that M. smegmatis aggregation was dependent on carbon source type and availability. In particular, glycerol catabolism induces
aggregation while pyruvate or amino acid catabolism leads to growth as dispersed cells. In contrast, oxygen availability does not induce changes in aggregation state. Currently, we are performing experiments in order to elucidate the genetic regulators that trigger aggregation in response to glycerol catabolism.
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Nontuberculous mycobacterial (NTM) pulmonary infections are emerging as a global health problem and pose a threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis, chronic obstructive pulmonary disease and bronchiectasis. Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) species account for 70-95% of the pulmonary NTM infections worldwide. Treatment options for these pathogens are limited, involve lengthy multidrug regimens of 12-18 months with parenteral and oral drugs, and their outcome is often suboptimal. Development of new drugs and improved regimens to treat NTM infections are thus greatly needed. In the last 2 years, the screening of compound libraries against M. abscessus in culture has led to the discovery of a number of different chemotypes that target MmpL3, an essential inner membrane transporter involved in the export of the building blocks of the outer membrane of all mycobacteria known as the mycolic acids. This perspective reflects on the therapeutic potential of MmpL3 in Mycobacterium tuberculosis and NTM and the possible reasons underlying the outstanding promiscuity of this target. It further analyzes the physiological and structural factors that may account for the apparent looser structure-activity relationship of some of these compound series against M. tuberculosis compared to NTM.
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The incidence of infections by rapidly growing mycobacteria has increased in recent decades. nontuberculous mycobacteria (NTM) represent over 190 species and subspecies and can cause both pulmonary and extrapulmonary symptoms. The Mycobacterium abscessus complex (MABC) is among the most drug-resistant mycobacterial species, and prompt diagnosis and effective eradication are burdensome. We present the clinical course of a 55-year-old female who was diagnosed with M. abscessus and explore her clinical diagnosis and possible treatment options. This case report emphasizes the challenges clinicians face in the prompt diagnosis of M. abscessus and discusses the treatment options in light of the recent guidelines.
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Nontuberculous mycobacteria (NTM) are emerging human pathogens, causing a wide range of clinical diseases affecting individuals who are immunocompromised and who have underlying health conditions. NTM are ubiquitous in the environment, with certain species causing opportunistic infection in humans, including Mycobacterium avium and Mycobacterium abscessus. The incidence and prevalence of NTM infections are rising globally, especially in developed countries with declining incidence rates of M. tuberculosis infection. Mycobacterium avium, a slow-growing mycobacterium, is associated with Mycobacterium avium complex (MAC) infections that can cause chronic pulmonary disease, disseminated disease, as well as lymphadenitis. M. abscessus infections are considered one of the most antibiotic-resistant mycobacteria and are associated with pulmonary disease, especially cystic fibrosis, as well as contaminated traumatic skin wounds, postsurgical soft tissue infections, and healthcare-associated infections (HAI). Clinical manifestations of diseases depend on the interaction of the host’s immune response and the specific mycobacterial species. This review will give a general overview of the general characteristics, vulnerable populations most at risk, pathogenesis, treatment, and prevention for infections caused by Mycobacterium avium, in the context of MAC, and M. abscessus.
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In recent years, the burden of nontuberculous mycobacteria pulmonary disease has increased worldwide. Nontuberculous mycobacteria - NTM infection is often misdiagnosed with Mycobacterium tuberculosis - MTB because of their similar clinical manifestations and preclinical manifestations. For MTB, the National Tuberculosis Program and the Ministry of Health (Vietnam) have a standard treatment regimen, while for NTM, an individualized treatment regimen based on infectious NTM species. Therefore, accurate identification of the causative NTM species can help clinicians choosing an effective treatment regimen. Among 122 suspected NTM samples collected at National Hospital 74, we successfully identified 115 strains belonging to NTM. Analytical DNA sequences, building phylogenetic trees were analyzed by Bioedit, ClustalX2, and MEGA-X software; comparing and identifying reference species from gene bank were used BLAST-NCBI. Slow-growing mycobacteria accounted for 61.7%, consists of Mycobacterium avium complex (37.4%), Mycobacterium lentiflavum (7.0%), Mycobacterium simiae (7.0%), Mycobacterium gordonae complex (5.2%) and other species less than 2.0%. The detection rate of rapid-growing mycobacteria was 38.3% including Mycobacterium abscessus complex (31.3%), and Mycobacterium fortuitum (7.0%). The most prevalent NTM species belonged to Mycobacterium avium complex and Mycobacterium abscessus complex (68.7%). The proportion of NTM infection in patients 50 years and older is 2.3 times higher than in patients under 50 years. This proportion is 5 times higher in females while there is no significant difference in males.
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